Atherosclerosis is a multifactorial disease developing preferentially in subjects presenting biochemical risks factors including smoking, hypertension, diabetes mellitus, hypercholesterolemia, elevated plasma low density lipoprotein (LDL) and triglycerides, hyperfibrinogenemia and hyperglycemia, among others. Atherosclerotic lesions develop over a number of decades in humans, leading to complications such as coronary and cerebral ischemic and thromboembolic diseases and myocardial and cerebral infarction. To date, cardiovascular disease is the leading cause of morbidity and mortality in industrialised countries and progresses steadily in emerging countries, with coronary atherosclerosis being the main underlying pathology. Currently, therapy of atherosclerosis is not completely efficient to prevent disease development and complication.
Atherosclerosis develops through the sequential interplay of at least three pathological processes: foam cell differentiation, inflammatory reaction and cell proliferation.
In humans and in various animal models, one of the earliest detectable events in the first of these processes is the recruitment of mononuclear phagocytes and lymphocytes to the intact endothelial lining of large arteries. Enhanced adhesion and accumulation of blood monocytes into the intima is then accompanied by a change in cell phenotype, where they transform into macrophages. The latter engulfs lipids and stores them as cytoplasmic droplets, thus becoming “foam cells”. The formation of such foam cells is a key stage in the development of early fatty streak lesions, and hence is a central event in atherogenesis.
The type B scavenger receptor CD36, which is known to have multiple functions, is recognised to play a key role in scavenging oxidized low density lipoproteins into monocytes/macrophages.
Growth hormone releasing peptides (GHRPs), which consist of a family of small synthetic peptides modelled from Met-enkephalin, possess potent and dose dependent growth hormone-releasing activity and significant prolactin and corticotropin-releasing effects (see Horm. Res. 51(suppl. 3), 9 (1999)).
The neuroendocrine activities of GHRPs are mediated by a specific G protein-coupled receptor identified as Ghrelin receptor expressed in hypothalamus and pituitary gland (see Horm. Res. 56(suppl. 1), 93 (2001)). However, GHRPs also provide a cardioprotective effect against cardiac ischemia in growth hormone (GH) deficient or aged rats. This protective activity is not coupled to any apparent stimulation of the somatotropic function, suggesting a direct myocardial action of these peptides (see Eur. J. Pharmacol. 334, 201 (1997)).
A study of GHRP binding sites in the cardiovascular system found that hexarelin, a hexapeptide member of the GHRP family, binds to a glycosylated membrane protein of 84 kD distinct from the Ghrelin receptor (see Circ. Res. 85, 796 (1999)). This protein was later identified as the CD36 receptor (see Circ. Res. 90, 844 (2002)).
None of the above-mentioned prior art suggests that GHRPs, or their synthetic analogues, can be employed to inhibit the lipid-scavenging function of the receptor CD36, thereby providing utility in the treatment and prevention of atherosclerosis, hypercholesterolemia and related diseases.